Intracellular retention and degradation of the epidermal growth factor receptor, two distinct processes mediated by benzoquinone ansamycins

Epidermal growth factor (EGF) stimulates the growth of various types of cel ls via its cell surface tyrosine kinase receptor, The EGF receptor (EGF-R) has an oncogenic potential when overexpressed in a wide range of tumor cell s. Geldanamycin (GA) and herbimycin (HA), specific inhibitors of the cytoso lic chaperone HSP 90 and its endoplasmic reticulum homologue GRP 94, were s hown to accelerate degradation of the EGF-R and of its homologue p185(c-erb B-2). Here we compared the effects of GA and HA on intracellular degradatio n and maturation of EGF-R. By using an inhibitor of proteasomal degradation , we learned that GA, but not HA, blocks processing of newly synthesized EG F-R, The effects of GA and HA on receptor degradation are mediated by the c ytosolic portion of EGF-R and could be conferred to the erythropoietin rece ptor (EPO-R), by employing the respective chimera. Neither HA nor GA affect ed stability of newly synthesized EGF-R lacking the cytosolic domain (Ex EG F-R), but GA caused intracellular retention of this mutant. Taken together, our results imply that GA has two distinct targets of action on the EGF-R, one for promoting its degradation and another for mediating its intracellu lar retention. Apparently, degradation of the EGF-R mediated by GA or HA re quires the presence of the EGF-R cytosolic domain, whereas intracellular re tention in the presence of GA is coupled to the extracellular domain of the EGF-R.